Molecular epidemiology and resistance mechanisms of tigecycline-non-susceptible Acinetobacter baumannii isolated from a tertiary care hospital in Chongqing, China.

We studied 34 isolates of Tigecycline-Non-Susceptible A. baumannii (TNAB) obtained from clinical specimens at a large tertiary care hospital in Chongqing, China. These 34 strains belonged to 8 different clones including ST195 (35.3%) and ST208 (17.7%). EBURST analysis found that these 8 ST types belonged to the Clonal Complex 92. Tigecycline resistance-associated genes adeR, adeS, adeL, adeN, rrf, rpsJ, and trm were detected in most strains. The expression level of the resistance-nodulation-cell division (RND) efflux pumps in TNAB strains was higher than the reference strain ATCC19606. 58.8% of strains had a decrease in the tigecycline minimum inhibitory concentration (MIC) after the addition of carbonyl cyanide 3-chlorophenylhydrazone (CCCP). The TNAB strains in our hospital have a high degree of affinity and antibiotic resistance. Regular surveillance should be conducted to prevent outbreaks of TNAB epidemics.

Regulatory role of oxidative stress in retrorsine - Induced apoptosis and autophagy in primary rat hepatocytes.

Pyrrolizidine alkaloids (PAs) are a group of naturally occurring alkaloids widely present in plants. PAs are highly hepatotoxic and have been documented to cause many incidents of human and animal poisoning. Retrorsine (RTS) is a pyrrolizidine alkaloid (PA) derived from the Compositae Senecio, which has been shown to cause hepatotoxicity. Human liver poisoning occurs through the consumption of RTS-contaminated food, and animals can also be poisoned by ingesting RTS-containing toxic plants. The mechanism of RTS-induced liver toxicity is not fully understood. In this study, we demonstrated that RTS-induced oxidative stress plays a pivotal role in RTS-induced liver toxicity involving apoptosis and autophagy. The results showed that RTS treatment in the cultured Primary rat hepatocytes caused cytotoxicity and release of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in a time- and dose-dependent manner. Our study showed that treatment of RTS induced ROS and MDA (malondialdehyde, a lipid peroxidation marker) in the hepatocytes, and reduced antioxidant capacity (GSH content, SOD activity), suggesting RTS treatment caused oxidative stress response in the hepatocytes. Furthermore, we found that RTS induced apoptosis and autophagy in the hepatocytes, and RTS-induced apoptosis and autophagy could be alleviated by ROS scavenger N-acetylcysteine (NAC) and the MAPK pathway inhibitors suggesting ROS/MAPK signaling pathway plays a role in RTS induced apoptosis and autophagy. Collectively, this study reveals the regulatory mechanism of oxidative stress in RTS-induced apoptosis and autophagy in the hepatocytes, providing important insights of molecular mechanisms of hepatotoxicity induced by RTS and related pyrrolizidine alkaloids in liver. This mechanism provides a basis for the prevention and treatment of PA poisoning in humans and animals.

Assessment of surgical strategies for management of complicated strabismus reoperation in Graves' ophthalmopathy.

PURPOSE: Strabismus reoperation in Graves' ophthalmopathy (GO) is complicated and challenging. The purpose of this study was to evaluate the various surgical strategies of strabismus reoperation and their outcomes in patients with GO. METHODS: A retrospective study was conducted on strabismus reoperations performed at the Zhongshan Ophthalmic Center of Sun Yat-sen University, Guangzhou, China from 2008 to 2018. Data collected included sex, age at surgery, duration of deviation, ocular alignment, ocular motility, various surgical procedures performed and surgical outcomes. Surgical methods included rectus recession for newly developed strabismus, rectus resection for undercorrection and anterior advancement of a previously recessed rectus for overcorrection. Surgical success was defined as an absence of diplopia, a horizontal deviation of ≤ 10 prism diopters (PD) and a vertical deviation of ≤ 5 PD at distance in primary and reading positions. RESULTS: Of the 153 GO patients receiving strabismus surgery, 27 cases (20 males, 7 females) underwent reoperation for strabismus, with a reoperation rate of 17.6%. Success rates of reoperation in patients with a previous undercorrection and overcorrection were 45% and 71.4%, respectively. Success rates of rectus recession, rectus resection and anterior advancement were 47.1%, 66.7% and 50%, respectively. Two patients underwent the third surgery. The overall success rate was 51.9%. CONCLUSIONS: Rectus recession is an effective method for GO patients with newly-developed strabismus. Rectus resection may benefit some patients with undercorrection who underwent a maximal degree of rectus recession. Anterior advancement of a previously recessed rectus is effective for cases with overcorrection.

Neuroinflammation with increased glymphatic flow in a murine model of decompression sickness.

This project investigated glial-based lymphatic (glymphatic) function and its role in a murine model of decompression sickness (DCS). DCS pathophysiology is traditionally viewed as being related to gas bubble formation from insoluble gas on decompression. However, a body of work implicates a role for a subset of inflammatory extracellular vesicles, 0.1 to 1 µm microparticles (MPs) that are elevated in human and rodent models in response to high gas pressure and rise further after decompression. Herein, we describe immunohistochemical and Western blot evidence showing that following high air pressure exposure, there are elevations of astrocyte NF-κB and microglial-ionized calcium-binding adaptor protein-1 (IBA-1) along with fluorescence contrast and MRI findings of an increase in glymphatic flow. Concomitant elevations of central nervous system-derived MPs coexpressing thrombospondin-1 (TSP) drain to deep cervical nodes and then to blood where they cause neutrophil activation. A new set of blood-borne MPs are generated that express filamentous actin at the surface that exacerbate neutrophil activation. Blood-brain barrier integrity is disrupted due to activated neutrophil sequestration that causes further astrocyte and microglial perturbation. When postdecompression node or blood MPs are injected into naïve mice, the same spectrum of abnormalities occur and they are blocked with coadministration of antibody to TSP. We conclude that high pressure/decompression causes neuroinflammation with an increased glymphatic flow. The resulting systemic liberation of TSP-expressing MPs sustains the neuroinflammatory cycle lasting for days.NEW & NOTEWORTHY A murine model of central nervous system (CNS) decompression sickness demonstrates that high gas pressure activates astrocytes and microglia triggering inflammatory microparticle (MP) production. Thrombospondin-expressing MPs are released from the CNS via enhanced glymphatic flow to the systemic circulation where they activate neutrophils. Secondary production of neutrophil-derived MPs causes further cell activation and neutrophil adherence to the brain microvasculature establishing a feed-forward neuroinflammatory cycle.

Metabolomic analysis and antibacterial and antioxidant activities of three species of Artemisia plants in Tibet.

BACKGROUND: Artemisia is important medicinal plants in China and are widely used in medicine, agriculture, and food. Pharmacologically active components of the plants remain to be investigated. METHODS: This study sought to identify and compare the chemical constituents of three species of Artemisia in Tibet using a widely-targeted metabolomics approach and their antibacterial and antioxidant capacities were determined. RESULT: A total of 1109 metabolites within 10 categories were detected from the three species of Artemisia, including lipids, amino acids, nucleotides, flavonoids, terpenes, coumarins, organic acids, and phenolic acids. 732 different metabolites have been identified between Artemisia sieversiana and Artemisia annua, 751 different metabolites were identified between Artemisia wellbyi and A. sieversiana, and 768 differential metabolites were differentially detected from A. wellbyi and A. annua. Differentially identified compounds included flavonoids, phenolic acids, artemisinins and coumarin. A. annua contained the highest relative content of artemisinin among three Artemisia. The antimicrobial experiments showed that the three Artemisia species had strong antibiotic activities against Bacillus subtilis, Escherichia coli, Staphylococcus aureus, Proteus mirabilis and Pseudomonas aeruginosa. The biochemical analysis showed that the three species of Artemisia have strong antioxidant capacity. CONCLUSIONS: This is the first reported attempt to comparatively determine the types of the metabolites of the three widely distributed Artemisia species in Tibet. The information should help medicinal research and facilitate comprehensive development and utilization of Artemisia species in Tibet.

Divergent contributions of coding and noncoding sequences to initial high-altitude adaptation in passerine birds endemic to the Qinghai-Tibet Plateau.

Early events in the evolution of an ancestral lineage can shape the adaptive patterns of descendant species, but the evolutionary mechanisms driving initial adaptation from an ancestor remain largely unexplored. High-altitude adaptations have been extensively explored from the viewpoint of protein-coding genes; however, the contribution of noncoding regions remains relatively neglected. Here, we integrate genomic and transcriptomic data to investigate adaptive evolution in the ancestor of three high-altitude snowfinch species endemic to the Qinghai-Tibet Plateau. Our genome-wide scan for adaptation in the snowfinch ancestor identifies strong adaptation signals in functions of development and metabolism for the coding genes, but in functions of the nervous system development for noncoding regions. This pattern is exclusive to the snowfinch ancestor compared to a control ancestral lineage subject to weak selection. Changes in noncoding regions in the snowfinch ancestor, especially those nearest to coding genes, may be disproportionately associated with the differential expression of genes in the brain tissue compared to other tissues. Extensive gene expression in the brain tissue can be further altered via genetic regulatory networks of transcription factors harbouring potential accelerated regulatory regions (e.g., the development-related transcription factor YEATS4). Altogether, our study provides new evidence concerning how coding and noncoding sequences work through decoupled pathways in initial adaptation to the selective pressure of high-altitude environments. The analysis highlights the idea that noncoding sequences may be promising elements in facilitating the rapid evolution and adaptation to high altitudes.

Averaging Strategy for Interpretable Machine Learning on Small Datasets to Understand Element Uptake after Seed Nanotreatment.

Understanding plant uptake and translocation of nanomaterials is crucial for ensuring the successful and sustainable applications of seed nanotreatment. Here, we collect a dataset with 280 instances from experiments for predicting the relative metal/metalloid concentration (RMC) in maize seedlings after seed priming by various metal and metalloid oxide nanoparticles. To obtain unbiased predictions and explanations on small datasets, we present an averaging strategy and add a dimension for interpretable machine learning. The findings in post-hoc interpretations of sophisticated LightGBM models demonstrate that solubility is highly correlated with model performance. Surface area, concentration, zeta potential, and hydrodynamic diameter of nanoparticles and seedling part and relative weight of plants are dominant factors affecting RMC, and their effects and interactions are explained. Furthermore, self-interpretable models using the RuleFit algorithm are established to successfully predict RMC only based on six important features identified by post-hoc explanations. We then develop a visualization tool called RuleGrid to depict feature effects and interactions in numerous generated rules. Consistent parameter-RMC relationships are obtained by different methods. This study offers a promising interpretable data-driven approach to expand the knowledge of nanoparticle fate in plants and may profoundly contribute to the safety-by-design of nanomaterials in agricultural and environmental applications.

Circ_0071589 contributes to growth, angiogenesis, and metastasis of colorectal cancer through regulating miR-296-5p/EN2 axis.

To explore the function and regulation mechanism of circ_0071589 in colorectal cancer (CRC). The expression levels of circ_0071589, microRNA-296-5p (miR-296-5p), and Engrailed-2 (EN2) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was performed to check the protein levels of EN2 and apoptosis-related proteins. Cell colony formation and 5-Ethynyl-29-deoxyuridine (EdU) assay were used to exhibit cell proliferation. Cell apoptosis was shown by flow cytometry. Tube formation assay manifested the angiogenesis ability of CRC cells. Transwell assay demonstrated cell migration and invasion. The interaction between miR-296-5p and circ_0071589 or EN2 was identified by dual-luciferase reporter assay. The effect of circ_0071589 on tumor formation was demonstrated by in vivo tumor formation experiments. Immunohistochemical (IHC) assay was used to detect the positive cell rate of Ki67 in tumor tissue. Circ_0071589 was upregulated in CRC tissue and cells. Circ_0071589 knockdown repressed CRC cells proliferation, angiogenesis, migration, invasion, and promoted cell apoptosis. MiR-296-5p was downregulated in CRC tissue and cells. And miR-296-5p inhibitor could reverse the malignant phenotypes and angiogenesis inhibition of CRC cells caused by circ_0071589 knockdown. Additionally, miR-296-5p decreased CRC cell colony formation, EdU-positive cells, angiogenesis, and increased cell apoptosis through reducing the expression level of EN2. Finally, circ_0071589 silencing inhibited tumor formation in vivo. Circ_0071589 upregulated EN2 expression through sponging miR-296-5p, thereby promoting the malignant phenotype and angiogenesis of CRC cells, which provided a new target for the treatment of CRC.

swnk plays an important role in the biosynthesis of swainsonine in Metarhizium anisopliae.

OBJECTIVE: Swainsonine (SW) is the principal toxic ingredient of locoweeds, and is produced by multiple fungi. A key enzyme in the SW synthesis pathway is a hybrid swnk/nrps. To analyze the role of swnk in the SW biosynthesis pathway of Metarhizium anisopliae. RESULTS: The concentration of SW and the swnk expression in M. anisopliae fermentation from 1st to 7th day were determined using LC-MS and RT-qPCR, respectively. M. anisopliae had the highest SW content and swnk expression on the 5th day of fermentation; Mutant strain (MT) were obtained by PEG-mediated homologous recombination (HR) which knocked out swnk in the wild-type (WT) strain. Complemented-type (CT) strain were obtained by transforming a modified PUC19 complementation vector containing the geneticin (G418) resistance gene and swnK. SW was not detected in the MT strain and reverted to its original level in the CT strain; A Psilent-1 plasmid with Benomyl (ben)-resistant that was used interfered with swnk of WT strain. The level of SW was markedly diminished in the RNAi strain. RNAi of swnk affects the formation of the cell wall in M. anisopliae. CONCLUSION: These results indicate that swnk plays a crucial role in the SW biosynthesis of M. anisopliae.

Imaging of the meningeal lymphatic network in healthy adults: A 7T MRI study.

BACKGROUND AND PURPOSE: Meningeal lymphatic vessels (MLVs) along the dural venous sinuses are suspected to be important in connecting the glymphatic and peripheral lymphatic system. Understanding the topography of MLVs may clarify the role of the glymphatic system in neurological diseases. The aim of this analysis was to use high resolution pre- and post-contrast FLAIR 7T MRI to identify and characterize the morphology of MLV in a cohort of healthy volunteers. MATERIALS AND METHODS: MRI examinations of seventeen healthy volunteers enrolled as controls in a larger 7T MRI study were reviewed. Pre- and post-contrast 3-D FLAIR subtractions and MP2RAGE sequences were spatially normalized and reviewed for signal intensity and enhancement patterns within putative MLVs along pre-determined dural and venous structures. Frequency of occurrence of MLVs at the above-described locations and patterns of their enhancement were analyzed. RESULTS: Putative MLVs are commonly located along the superior sagittal sinus (SSS) and cortical veins. A "fixed enhancement" signal pattern was more frequent at these locations (p<.05). The morphology of MLVs along the SSS qualitatively changes in an antero-posterior direction. Lack of signal was more frequent along the straight and transverse sinuses (p<.05). CONCLUSION: Putative MLVs in healthy individuals are concentrated along the SSS and cortical veins. FLAIR signal and enhancement characteristics suggest these structures may transport proteinaceous fluid. Pathways connecting MLVs to cervical lymph nodes however remain unclear.

Zhizhu decoction alleviates slow transit constipation by regulating aryl hydrocarbon receptor through gut microbiota.

CONTEXT: Slow transit constipation (STC), the most common type of constipation, seriously affects the life of patients. Zhizhu decoction (ZZD), a traditional Chinese medicine compound, has is effective against functional constipation, but the mechanism is still unclear. OBJECTIVE: This research explores the mechanism of ZZD on STC from the perspective of metabolomics and gut microbiota. MATERIALS AND METHODS: Fifty-four C57BL/6 mice were randomly divided into six groups (n = 9): control (control); STC (model); positive control (positive); low-dose (5 g/kg; L-ZZD), medium-dose (10 g/kg; M-ZZD), and high-dose (20 g/kg; H-ZZD) ZZD treatment. Following treatment of mice with ZZD for two weeks, the changes in intestinal motility, colon histology, intestinal neurotransmitters, and aryl hydrocarbon receptor (AHR) pathway determined the effects of ZZD on the pathophysiology of STC. LC-MS targeting serum metabolomics was used to analyze the regulation of ZZD on neurotransmitters, and 16S rRNA high-throughput sequencing was used to detect the regulation of the gut microbiome. RESULTS: ZZD had the highest content of naringin (6348.1 mg/L), and could significantly increase the 24 h defecations (1.10- to 1.42-fold), fecal moisture (1.14-fold) and intestinal transport rate (1.28-fold) of STC mice, increased the thickness of the mucosal and muscular tissue (1.18- to 2.16-fold) and regulated the neurotransmitters in the colon of STC mice. Moreover, ZZD significantly activated the AHR signaling pathway, and also affected the composition of gut microbiota in STC mice. DISCUSSION AND CONCLUSIONS: The beneficial effect and the possible mechanism of ZZD on STC could provide a theoretical basis for the broader clinical application of ZZD.

CoFe2O4nanoparticles dispersed on carbon rods derived from cotton for high-efficiency microwave absorption.

Biomass-derived carbon materials have received a surge of scientific attention to develop lightweight and broadband microwave absorbers. Herein, rodlike porous carbon materials derived from cotton have been fabricated with uniformly dispersed CoFe2O4nanoparticles via facile and scalable process. The combination of magnetic particles and carbonaceous material is advantageous to realize the magnetic-dielectric synergistic effect which could effectively promote the dissipation of incident waves, giving rise to an optimal reflection loss value of -48.2 dB over a qualified bandwidth (4.8 GHz) at 2.5 mm. The cotton-derived carbon rods with conductive network not only act as a supporter to carry the CoFe2O4nanoparticles, but also provide massive heterointerfaces to facilitate the interfacial polarization. In consideration of the renewable and abundant resource of cotton, the as-prepared CoFe2O4/C composites would meet the increasing demand of lightweight and highly efficient microwave absorbers.

Can Traditional Straight-leg Swaddling Influence Developmental Dysplasia of the Femoral Trochlea? An In Vivo Study in Rats.

BACKGROUND: It has been reported that trochlear dysplasia occurs very early in development, and environmental factors like swaddling may cause developmental dysplasia of the hip, which is associated with a shallower trochlear groove. However, to our knowledge, there are no definitive studies about the relationship between trochlear dysplasia and traditional straight-leg swaddling. QUESTIONS/PURPOSES: Using a rat model of femoral trochlear dysplasia, we asked: Does straight-leg swaddling for 1 and 2 weeks in newborn Wistar rats alter the femoral trochlea with respect to (1) gross morphology, (2) histologic appearance, as well as (3) trochlear sulcus angle, width, and depth? METHODS: Eighty-four newborn Wistar rats (44 females and 40 males) were divided into two equal groups: 42 in the unswaddled group and 42 in the swaddled group; each group was comprised of 22 females and 20 males. In the swaddled group, the rats were wrapped in surgical tape to maintain hip and knee extension to simulate traditional human straight-leg swaddling. To determine whether longer periods of swaddling were associated with more severe trochlear dysplasia, 21 rats in each group were euthanized at 1 and 2 weeks, respectively, and the gross morphology of the femoral trochlea was observed by one observer blinded to condition. Then hematoxylin and eosin staining of the femoral trochlea was performed and the distribution and number of the chondrocytes of the trochlear groove were viewed through a microscope. The trochlear sulcus angles, depth, and width were measured by an experienced technician blinded to condition. RESULTS: By observing the gross morphology, we found that the trochlear groove in the swaddled group became qualitatively flatter compared with the unswaddled group at 1 week, and at 2 weeks, the trochlear groove became much shallower. At 1 and 2 weeks, histologic examinations showed obvious qualitative changes in the distribution and number of chondrocytes of the trochlear groove in the swaddled than in the unswaddled groups. In the swaddled group, trochlear dysplasia was more common at 2 weeks, occurring in 62% (26 of 42 [16 of 22 females and 10 of 22 males]) versus 33% (14 of 42 [8 of 22 females and 6 of 20 males]) at 1 week. At 1 week, the swaddled group showed more trochlear dysplasia compared with the unswaddled group as measured by angle of the trochlear groove (137° ± 6° versus 132°± 3.6°, mean difference 5° [95% confidence interval 2.9° to 7.2°]; p < 0.001), depth of the trochlear grove (0.28 ± 0.04 mm versus 0.31 ± 0.02 mm, mean difference 0.03 mm [95% CI 0.01 to 0.04]; p < 0.001). At 2 weeks, the swaddled group showed more severe trochlear dysplasia than at 1 week compared with the unswaddled group as measured by the angle of the trochlear groove (135° ± 6.0° versus 128° ± 4.8°, mean difference 7° [95% CI 5.7° to 10.4°]; p < 0.001), depth of the trochlear grove (0.32 ± 0.04 mm versus 0.36 ± 0.02 mm, mean difference 0.04 mm [95% CI 0.03 to 0.06]; p < 0.001). There was no difference in the width of the trochlear sulcus between the swaddled and the unswaddled groups at 1 week (1.29 ± 0.14 mm versus 1.30 ± 0.12 mm, mean difference 0.01 mm [95% CI -0.05 to 0.07]; p = 0.73) and 2 weeks (1.55 ± 0.12 mm versus 1.56 ± 0.12 mm, mean difference 0.01 mm [95% CI -0.05 to 0.07]; p = 0.70). CONCLUSION: Our results indicate that traditional straight-leg swaddling could induce trochlear dysplasia in this model of newborn rats. With an increased swaddling time of 2 weeks, more severe trochlear dysplasia appeared in the swaddled group. CLINICAL RELEVANCE: Our findings suggest that traditional straight-leg swaddling may impair trochlear development in the human neonate and lead to trochlear dysplasia in infants. We believe our animal model will be useful in future work to observe and study the change of cartilage and subchondral bone in each stage of the development of trochlear dysplasia and the change of mechanotransduction-associated proteins (such as, TRPV4/ Piezo1 and CollagenⅡ) in cartilage and subchondral osteocytes. It will also be helpful to further investigate the mechanism of developmental femoral trochlea dysplasia caused by biomechanical changes.

What is the relationship between the breech presentation and femoral trochlear dysplasia? An experimental study of the breech presentation model in neonatal rats.

BACKGROUND: The relationship between breech presentation and trochlear dysplasia has been confirmed. However, the pathological process of breech-related trochlear dysplasia remains unclear. This study aimed to establish an animal model to simulate breech presentation and to analyze the pathological process of the femoral trochlea. MATERIALS AND METHODS: One hundred and twenty neonatal rats were randomly assigned into a control group and two experimental groups that were swaddled (using surgical tape) to keep the hip flexed and knees extended to simulate human breech presentation for the 5 days (short Swaddling) and the 10 days (prolonged Swaddling) of life. Gross and cross-sectional observation, histological staining measurement in two experimental time points (5 and 10 days after birth) were conducted to evaluate the morphological changes of the femoral trochlea. RESULTS: The incidence of trochlear dysplasia increased with the Swaddling time. Rats in the prolonged Swaddling group had the high prevalence of trochlea dysplasia (52 of 60), followed by short Swaddling group (42 of 60). Gross and cross-sectional observation showed a shallower trochlea groove in two experimental groups. Histologicalstaining measurement indicated that the trochlear sulcus angle and trochlear sulcus depth were significantly different between the experimental group and the control group since day 5 and day 10. CONCLUSION: In this model, breech presentation had an adverse effect on neonatal knees and could induce trochlear dysplasia. In addition, this study also showed that the more time in breech presentation, the more incidence of trochlear dysplasia.

Alterations in the whole brain network organization after prenatal ethanol exposure.

BACKGROUND: People with fetal alcohol spectrum disorder (FASD) often have structural or functional alterations of the central nervous system, including changes in brain network organization. These have been associated with neuropsychological deficits, but outcomes are not consistent across studies. We used a rat model of FASD to assess brain network alterations in males and females following ethanol exposure during a prenatal period similar to the first half of gestation in humans. METHODS: Pregnant Long Evans rats were given an ethanol-containing or isocaloric non-ethanol diet from gestation day 6 to 20. Resting-state functional magnetic resonance imaging was performed on offspring in young adulthood. Graph theoretical analysis was used to assess properties associated with the whole brain network organization, with a focus on segregation, integration, and small-world organization-a feature which allows specialized local information processing (segregation) and simultaneously efficient global information sharing (integration). RESULTS: Ethanol-exposed females showed a significant decrease in small-worldness compared with control females or with ethanol-exposed males. Compared to control females, the proportion of animals with atypically high path length (1 standard deviation higher than the grand average) was significantly higher in ethanol-exposed females, indicating that the alteration in small-world organization is driven by decreased network integration. No significant effects were seen in males. CONCLUSION: The results revealed that prenatal ethanol exposure disrupts the balance between network segregation and integration in young adult female rats. The whole brain network is less integrated after ethanol exposure in the females, suggesting wide-spread reduction of long-range regional communication.

Altered Forebrain Functional Connectivity and Neurotransmission in a Kinase-Inactive Met Mouse Model of Autism.

MET, the gene encoding the tyrosine kinase receptor for hepatocyte growth factor, is a susceptibility gene for autism spectrum disorder (ASD). Genetically altered mice with a kinase-inactive Met offer a potential model for understanding neural circuit organization changes in autism. Here, we focus on the somatosensory thalamocortical circuitry because distinct somatosensory sensitivity phenotypes accompany ASD, and this system plays a major role in sensorimotor and social behaviors in mice. We employed resting-state functional magnetic resonance imaging and in vivo high-resolution proton MR spectroscopy to examine neuronal connectivity and neurotransmission of wild-type, heterozygous Met-Emx1, and fully inactive homozygous Met-Emx1 mice. Met-Emx1 brains showed impaired maturation of large-scale somatosensory network connectivity when compared with wild-type controls. Significant sex × genotype interaction in both network features and glutamate/gamma-aminobutyric acid (GABA) balance was observed. Female Met-Emx1 brains showed significant connectivity and glutamate/GABA balance changes in the somatosensory thalamocortical system when compared with wild-type brains. The glutamate/GABA ratio in the thalamus was correlated with the connectivity between the somatosensory cortex and the thalamus in heterozygous Met-Emx1 female brains. The findings support the hypothesis that aberrant functioning of the somatosensory thalamocortical system is at the core of the conspicuous somatosensory behavioral phenotypes observed in Met-Emx1 mice.

Functional Connectivity and Metabolic Alterations in Medial Prefrontal Cortex in a Rat Model of Fetal Alcohol Spectrum Disorder: A Resting-State Functional Magnetic Resonance Imaging and in vivo Proton Magnetic Resonance Spectroscopy Study.

Prenatal ethanol exposure alters brain structure, functional connectivity, and behavior in humans and rats. Behavioral changes include deficits in executive function, which requires cooperative activity between the frontal cortices and other brain regions. In this study, we analyzed the functional connectivity and neurochemical levels of the prefrontal cortex (PFC) using resting-state functional magnetic resonance imaging (rsfMRI) and proton magnetic resonance spectroscopy (1H-MRS) in ethanol-exposed (Eth) and control (Ctr) rats. Pregnant Long-Evans rats were fed a liquid diet containing ethanol (2.1-6.46% v/v ethanol) from gestational days 6 to 21 (Eth). Ctr animals received an isocaloric, isonutritive liquid diet. In young adulthood, male and female offspring underwent in vivo MRI using a 7.0-Tesla system. 1H-MRS from the PFC and whole brain rsfMRI were obtained on the animals. Seed-based functional connectivity analysis was performed with seeds placed in the PFC, matching the voxel of MRS. Male, but not female, Eth rats showed less functional connectivity between PFC and dorsal striatum than Ctr animals. In Eth males glucose levels were significantly lower, and in Eth females lower levels of phosphorylcholine but an increased gamma-aminobutyric acid/glutamate ratio were observed in the PFC compared with Ctr animals. Prenatal ethanol alters brain metabolism and functional connectivity of the PFC in a sex-dependent manner.

Effects of Early Alcohol Exposure on Functional Organization and Microstructure of a Visual-Tactile Integrative Circuit.

BACKGROUND: Children with fetal alcohol spectrum disorders (FASD) often have deficits associated with multisensory processing. Because ethanol (EtOH) disrupts activity-dependent neuronal plasticity, a process that is essential for refining connections during cortical development, we hypothesize that early alcohol exposure results in alterations in multisensory cortical networks, which could explain the multisensory processing deficits seen in FASD. Here, we use a gyrencephalic animal model to test the prediction that early alcohol exposure alters the functional connectivity and microstructural features of the rostral posterior parietal cortex (PPr), a visual-tactile integrative area. METHODS: Ferrets were exposed to moderate doses of EtOH during the brain growth spurt period. Functional connectivity and microstructural features were assessed using resting-state functional magnetic resonance imaging and ex vivo diffusion kurtosis imaging (DKI), respectively, when the animals reached juvenile age and adulthood, respectively. RESULTS: While the whole brain volume was smaller in alcohol-treated animals, the relative size of the frontal brain area was larger when compared to control animals. Altered functional connectivity was observed in alcohol-treated animals, where increased connectivity was observed between PPr and the region that provides its major visual inputs (the caudal portion of the parietal cortex), but not with the region that provides its major somatosensory inputs (tertiary somatosensory cortex). DKI revealed reduced microstructural tissue complexity in all investigated sensory areas of alcohol-treated animals. CONCLUSIONS: In this study, we observed alterations in cortical functional connectivity and microstructural integrity in a cortical area involved in multisensory processing in a ferret FASD model. These findings indicate an alteration in cortical networks that may be related to the multisensory processing deficiencies observed in FASD.

Better 4-year outcomes for anterior cruciate ligament reconstruction with double-layer versus single-layer bone-patellar tendon-bone allografts.

PURPOSE: To evaluate the results of anterior cruciate ligament reconstruction using a double-layer bone-patellar tendon-bone (DBPTB) graft. METHODS: Between 2010 and 2011, 98 patients underwent anterior cruciate ligament reconstruction with an allograft. Forty-seven of these patients received a DBPTB allograft and 51 received a traditional monolayer BPTB graft. Outcomes were evaluated at the end of a minimum 4-year follow-up in both groups using KT 1000 arthrometer measurements, Lachman and pivot-shift tests, the International Knee Documentation Committee form, and Lysholm scores. RESULTS: One patient (1/47, 2 %) in the DBPTB allograft group and six patients (6/51, 12 %) in the traditional monolayer BPTB graft were lost during follow-up because of graft rupture (n.s.). The mean side-to-side differences in the DBPTB and monolayer BPTB graft groups 4 years post-operatively were significantly different at 1.4 ± 1.3 and 1.7 ± 1.6 mm, respectively (p < 0.05). The DBPTB group performed significantly better than the BPTB group on the Lachman test, International Knee Documentation Committee knee score, and Lysholm scores (p < 0.05). CONCLUSIONS: The DBPTB allograft group achieved better outcomes than the traditional BPTB allograft group regarding success rate, anterior stability, and knee function. LEVEL OF EVIDENCE: Level II.

Neuroprotective Effects of Acetyl-L-Carnitine on Neonatal Hypoxia Ischemia-Induced Brain Injury in Rats.

Perinatal hypoxia ischemia (HI) is a significant cause of brain injury in surviving infants. Although hypothermia improves outcomes in some infants, additional therapies are needed since about 40% of infants still have a poor outcome. Acetyl-L-carnitine (ALCAR), an acetylated derivative of L-carnitine, protected against early changes in brain metabolites and mitochondrial function after HI on postnatal day (PND) 7 in a rat pup model of near-term HI injury. However, its efficacy in long-term structural and functional outcomes remains unexplored. We determined the efficacy of ALCAR therapy administered to rat pups after HI at PND 7, using both longitudinal in vivo magnetic resonance imaging and behavioral tests, in male and female rats. HI led to sex-specific behavioral impairment, with males exhibiting more global functional deficits than females. Interestingly, HI reduced the volume of the contralateral hemisphere in males only, suggesting that the brain injury is more diffuse in males than in females. Treatment with ALCAR improved both morphological and functional outcomes in both male and female rats. These results suggest that ALCAR may be a potential therapy for clinical use since the treatment attenuated the moderate injury produced under the experimental conditions used and improved the functional outcome in preclinical studies.